Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, affecting as many as 200 million individuals worldwide, with 779 million living at risk of infection. A new drug for schistosomiasis is urgently needed as praziquantel is currently the drug of last resort and the development of resistance cannot be ignored, particularly in view of its large-scale use in many endemic. Our long-term goal is to discover a new orally active single-dose antischistosomal drug with activities against all parasite stages and with a novel mechanism of action. The objective of this proposal is to identify one or more antischistosomal drug development candidates. To accomplish this objective, we will optimize four promising antischistosomal chemotypes. We will also continue our investigation into the host-mediated antischistosomal mode of action of aryl hydantoin drug candidate AR102. We propose four specific aims: 1) to synthesize and characterize target compounds; 2) to assess pharmacokinetic properties and antischistosomal activity of target compounds; 3) to further profile selected target compounds using more rigorous assays; and 4) to investigate the mode of action of drug candidate AR102. Compound design will be informed by existing SAR and will maximize structural diversity guided by prospective in silico physicochemical profiling. Based on iterative feedback from physicochemical profiling, in vitro ADME, and cytotoxicity (SA 1), ex vivo and in vivo antischistosomal activity and in vivo ADME (SA 2 and 3), new structural hypotheses will arise, and we will synthesize additional target compounds. Target compounds will progress through the various assays using clearly defined progression criteria. We suggest that this proposed research is innovative for several reasons First, the aryl hydantoins and ozonides have proven in vivo antischistosomal efficacy, but have very low ex vivo (in vitro) activity, the reverse of the usual situation where lead compounds have in vitro but no in vivo activity. Second, the azonine keto lactam chemotype and backup tricyclic imidazolidin-4-one compound series are examples of relatively rare medium-ring compounds (8 to 11 atoms). Third, we seek to demarcate the unique host-mediated mode of action of antischistosomal drug candidate AR102. The expected outcome from this work is to identify one or more antischistosomal drug development candidates effective against all parasite stages. For antischistosomal drug candidate AR102, we will define its host-mediated antischistosomal mode of action. This proposed research is significant because a new drug would be important in the chemotherapy of drug-resistant schistosomiasis and likely be valuable in integrated control programs to curb this parasitic disease.